Methods, systems, and devices for treating neuromas, fibromas, nerve entrapment, and/or pain associated therewith

ABSTRACT

A method in which a location is determined on the skin that is proximate to a sensory nerve that is associated with a painful condition. At least one needle of a cryogenic device is inserted into the location on the skin such that the needle is proximate to the sensory nerve. The device is activated such that the at least one needle creates a cooling zone about the sensory nerve, thereby eliminating or reducing severity of the painful condition.

CROSS-REFERENCES TO RELATED APPLICATIONS

The present application is a divisional application of U.S. patentapplication Ser. No. 14/218,146, filed on Mar. 18, 2014, which claimsthe benefit to U.S. Provisional Patent Application No. 61/800,478 filedMar. 15, 2013, entitled “Methods and Devices for Pain Management” and toU.S. Provisional Patent Application No. 61/801,268 filed Mar. 15, 2013,entitled “Cryogenic Blunt Dissection Methods and Devices,” the completedisclosures of which are incorporated herein by reference.

BACKGROUND OF THE INVENTION

The present invention is directed to medical devices, systems, andmethods, particularly for those which employ cold for treatment ofneuromas or fibromas associated with limb pain in a patient. Embodimentsof the invention include cryogenic cooling needles that can be advancedthrough skin or other tissues to treat neuromas and fibromas, and/or toinhibit transmission of pain signals.

Over 100 million patients in the United States suffer from chronic pain.Chronic pain conditions are often debilitating, taking a toll on apatient's physical and mental welfare. Though a variety of painmanagement techniques currently exist, the most common nonsurgicaloptions provide slow-acting and/or short-term relief. Medication, oftenin the form of non-steroidal anti-inflammatory drugs (NSAIDs) andopioids, comes with an array of side effects such as nausea andvomiting. Medication also presents the possibility of more seriouseffects such as increased risk of heart attack and stroke, and toleranceor dependency issues. Surgical strategies tend to be reserved for moresevere cases and are limited by the risks and complications typicallyassociated with surgery including bleeding, bruising, scarring, andinfection.

A nonsurgical, minimally invasive, long-lasting approach to chronic painmanagement is desirable. In general, it would be advantageous to provideimproved devices, systems, and methods for management of chronic and/oracute pain. Such improved techniques may avoid or decrease the systemiceffects of toxin-based neurolysis and pharmaceutical approaches, whiledecreasing the invasiveness and/or collateral tissue damage of at leastsome known pain treatment techniques.

BRIEF SUMMARY OF THE INVENTION

Many embodiments provide a novel, minimally invasive device and methodfor providing focused cold therapy to target peripheral sensory nervetissue that offers long-lasting pain relief through cryoanalgesia. Thedevice and method may operate on the cryobiology principle thatlocalized exposure to controlled moderately low temperature conditionscan alter tissue function. The device and therapy may treat nerves withlow temperatures via a cold probe in the form of an assembly of smalldiameter needles, creating a highly localized treatment zone around theprobe. This focused cold therapy (FCT) may create a conduction blockthat prevents nerve signaling. Further, preliminary studies haveprovided preliminary evidence of the device and method effectiveness onmotor nerves and have been shown to be safe with no seriousdevice-related adverse events.

In some embodiments, a system for treating a neuroma or other painfulcondition (e.g., nerve entrapment, plantar fasciitis, fibromas, or thelike) in a limb of a patient is provided. The system may include aneedle having a proximal end, a distal end, and a needle lumentherebetween. The needle may be configured for insertion proximate tothe nerve. A cooling fluid supply lumen may extend distally within theneedle lumen to a distal portion of the needle lumen. A cooling fluidsource may be couplable to the cooling fluid supply lumen to directcooling fluid flow into the needle lumen so that liquid from the coolingflow vaporizes within the needle lumen to provide cooling to the nervesuch that neuroma decreases in size and/or pain associated with theneuroma and experienced by the patient is reduced.

In some embodiments, the cooling flow may vaporize within the needlelumen to provide a cryozone having a cross-sectional area between 14-40mm². In some embodiments, the cross-sectional area may be between 20-36mm² or between 25-30 mm². The cryozone may be defined by a 0° C.isotherm (e.g., cooling zone). Optionally, the cooling flow may vaporizewithin the needle lumen to provide a cryozone having a volume between65-105 mm³, or between 80-90 mm³.

The system may further include a heating element coupled with a proximalportion of the needle. The heating element may be configured to deliverheating phases to the skin of the patient. A processor may be configuredto control the cooling fluid flow and the heating element in response tooperator input. The processor may be configured to provide a treatmentcycle in response to a treatment instruction. The treatment cycle mayinclude at least one heating phase and one cooling phase. A degree ofskin warmer throughout the treatment cycle may be provided. The degreeof skin warmer may comprises 25-42° C. skin warmer throughout thetreatment cycle. In some embodiments the skin warmer may be 30° C., 35°C., or 40° C.

The at least one heating phase may comprise a pre-warm phase with theheating element before the at least one cooling phase. The pre-warmphase may have a duration of 8-12 seconds or may end when the heatingelement reaches the skin warming temperature. The at least one coolingphase may have a duration between 20-65 seconds. In some embodiments, itmay be beneficial to have shorter duration cooling phases. Someembodiments may provide sufficient treatment with a 30 second, 35second, or 40 second cooling phase. In some embodiments, a 60 secondcooling phase may be used.

In some embodiments, the at least one cooling phase may have a durationof less than 40 seconds. The 40 second cooling phase may be sufficientto create a cryozone having a cross-sectional area between 14-40 mm². Insome embodiments, the at least one cooling phase may have a duration ofless than 40 seconds and may create a cryozone having a volume between65-105 mm³.

Optionally, the at least one heating phase may also include a post-warmphase. The post-warm phase may have a duration of 12-18 seconds.Preferably, the distal portion of the needle may have a temperature ofat least 0° C. at the end of the post-warm phase. In some embodiments,the needle may have a length of 5-14 mm. In some embodiments a 6-7 mm(e.g., 6.9 mm) needle may be used. In some embodiments where targettissues or nerves are deeper, one or more longer needles (e.g., 12 mmneedle(s)) may be used. Optionally, the processor may be configured toprovide an audio or visual alert at completion of a treatment cycle.

In further embodiments of the invention, a method for treating aneuroma, nerve entrapment, or other painful condition associated with anerve in a limb of a patient is provided. The method may includeidentifying a location of pain experienced by the patient and associatedwith the neuroma and/or nerve entrapment. Thereafter, the method mayinclude identifying the nerve based in-part on the identified locationand positioning a distal end of a cryogenic cooling needle having aneedle lumen proximal the nerve. A treatment cycle may then be deliveredto the target tissue with the cryogenic cooling needle. The treatmentcycle may comprise a cooling phase where cooling fluid flows into theneedle lumen so that liquid from the cooling flow vaporizes within theneedle lumen to provide cooling to the nerve such that the neuromadecreases in size and/or pain associated with the neuroma, nerveentrapment, or other painful condition is reduced.

In some embodiments, the treatment cycle may be configured to generate acryozone having a cross-sectional area between 14-40 mm². The cryozonemay be defined by a 0° C. isotherm. Optionally, the treatment cycle maybe configured to generate a cryozone having a volume between 65-105 mm³.

The method may include providing a degree of skin warmer throughout thedelivery of the treatment cycle, the degree of skin warmer may be 20-42°C. skin warmer throughout the treatment cycle. Optionally, the cryogeniccooling needle may further comprises a heating element coupled with aproximal portion of the needle and the treatment cycle may furthercomprises at least one heating phase. The at least one heating phase maycomprise a pre-warm phase with the heating element before the at leastone cooling phase. The pre-warm phase may have a duration of 8-12seconds.

The at least one cooling phase may have a duration of 20-65 secondsafter the pre-warm phase. The at least one cooling phase may have aduration of less than 40 seconds and may be configured to create acryozone having a cross-sectional area between 14-40 mm².

The at least one cooling phase may have a duration of less than 40seconds and may create a cryozone having a volume between 65-105 mm³.

In some embodiments the at least one heating phase further comprises apost-warm phase. The post-warm phase may have a duration of 12-18seconds. Preferably, the distal portion of the needle may have atemperature of at least 0° C. at the end of the post-warm phase. In someembodiments, the needle may have a length of 5-12 mm.

In further embodiments, a system for reducing pain experienced by apatient is provided. The pain may be associated with a compressed nerve.The system may include a plurality of needles, each having a lengthbetween 5-14 mm and being spaced apart by not more than 3 mm. Eachneedle may further include a proximal end, an distal end, and a needlelumen therebetween. A heating element may be coupled with a proximalportion of the each of the plurality of needles. The heating element maybe configured to deliver heating phases to the skin of the patient whenthe plurality of needles are inserted proximal to the nerve and atreatment cycle is being delivered to the nerve. A plurality of coolingfluid supply lumens may extend distally within the each of the pluralityof needle lumens to a distal portion of each of the plurality of needlelumens. A cooling fluid source may be coupleable to the plurality ofcooling fluid supply lumens to direct cooling fluid flow into theplurality of needle lumens so that liquid from the cooling flowvaporizes within the plurality of needle lumens to deliver adjacentcooling cycles to the nerve such that pain signals from the nerve areinterrupted. A processor may be configured to control the cooling fluidflow and the heating element in response to operator input. In someembodiments the plurality of needles may be 27 gauge needles or smaller(e.g., 30 gauge needles). The plurality of needles may be 11-13 mm inlength. Optionally, the plurality of needles may be 5-7 mm in length.

In further embodiments, a system for reducing pain experienced by apatient is provided. The pain may be associated with a compressed nerve.The system may include a first needle assembly. The first needleassembly may include a plurality of needles, each having a lengthbetween 10-14 mm and being spaced apart by not more than 3 mm (e.g., 2mm). Each needle may further include a proximal end, an distal end, anda needle lumen therebetween. A second needle assembly may include aplurality of needles, each having a length between 5-7 mm and beingspaced apart by not more than 3 mm (e.g., 2 mm). Each needle may furtherinclude a proximal end, an distal end, and a needle lumen therebetween.

A handle may have a needle assembly interface at a proximal end of thehandle for receiving either the first needle assembly and the secondneedle assembly. A cooling fluid source may be housed in the handle andmay be coupleable with the first needle assembly and the second needleassembly when attached to the handle to direct cooling fluid flow intothe plurality of needle lumens so that liquid from the cooling flowvaporizes within the plurality of needle lumens to deliver adjacentcooling phases to the nerve such that pain associated with thecompressed nerve is mitigated. A processor may be configured to controlthe cooling fluid flow in response to operator input.

Further features of the invention, its nature and various advantageswill be more apparent from the accompanying drawings and the followingdetailed description.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1A is a perspective view of a self-contained subdermal cryogenicremodeling probe and system, according to some embodiments of theinvention;

FIG. 1B is a partially transparent perspective view of theself-contained probe of FIG. 1A, showing internal components of thecryogenic remodeling system and schematically illustrating replacementtreatment needles for use with the disposable probe according to someembodiments of the invention;

FIG. 2A schematically illustrates exemplary components that may beincluded in the treatment system;

FIG. 2B is a cross-sectional view of the system of FIG. 1A, according tosome embodiments of the invention;

FIGS. 2C and 2D are cross-sectional views showing exemplary operationalmodes of the system of FIG. 2B;

FIGS. 3A-3E illustrate an exemplary embodiment of a clad needle probe,according to some embodiments of the invention;

FIGS. 4A-4C illustrate an exemplary method of introducing a cryogenicprobe to a treatment area, according to some embodiments of theinvention;

FIG. 4D illustrates an alternative exemplary embodiment of a sheath,according to some embodiments of the invention;

FIG. 5 illustrates an exemplary insulated cryoprobe, according to someembodiments of the invention;

FIGS. 6-9 illustrate exemplary embodiments of cryofluid delivery tubes,according to some embodiments of the invention;

FIG. 10 illustrates an example of blunt tipped cryoprobe, according tosome embodiments of the invention;

FIGS. 11 and 12 illustrate exemplary actuatable cryoprobes, according tosome embodiments of the invention;

FIG. 13 is a flow chart illustrating an exemplary algorithm for heatingthe needle probe of FIG. 3A, according to some embodiment of theinvention;

FIG. 14 is a flow chart schematically illustrating an exemplary methodfor treatment using the disposable cryogenic probe and system of FIGS.1A and 1B, according to some embodiments of the invention;

FIG. 15 illustrates the nerves of the lower leg and foot;

FIG. 16 shows the branching of the superficial peroneal nerve into theintermediate and medial cutaneous nerves;

FIGS. 17A-17B show further details of nerves located in the foot;

FIG. 18 shows innervation of the plantar aspect of the foot;

FIG. 19 shows the details of the intermediate dorsal cutaneous nerve;

FIG. 20 is a drawing of the dorsal aspect of the foot and illustratesthe territories of: the deep peroneal nerve (DPN), the lateral plantarnerve (LPN), the medial plantar nerve (MPN), the sural nerve (SN), andthe superficial peroneal nerve (SPN) via the medial and intermediatecutaneous nerves;

FIG. 21 shows an oblique coronal MR image of the subcutaneoussuperficial peroneal nerve branches and the great saphenous vein;

FIG. 22 shows a distal coronal MR image of the branches of the deepperoneal nerve for the first dorsal space; and

FIG. 23 shows another distal coronal MR image of the termination alongthe first toe of the medial cutaneous nerve and the medial plantarnerve.

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides improved medical devices, systems, andmethods. Embodiments of the invention may facilitate remodeling oftarget tissues disposed at and below the skin, optionally to treat painassociated with a sensory nerve. Embodiments of the invention mayutilize a handheld refrigeration system that can use a commerciallyavailable cartridge of fluid refrigerant. Refrigerants well suited foruse in handheld refrigeration systems may include nitrous oxide andcarbon dioxide. These can achieve temperatures approaching −90° C.

Sensory nerves and associated tissues may be temporarily impaired usingmoderately cold temperatures of 10° C. to −5° C. without permanentlydisabling the tissue structures. Using an approach similar to thatemployed for identifying structures associated with atrial fibrillation,a needle probe or other treatment device can be used to identify atarget tissue structure in a diagnostic mode with these moderatetemperatures, and the same probe (or a different probe) can also be usedto provide a longer term or permanent treatment, optionally by ablatingthe target tissue zone and/or inducing apoptosis at temperatures fromabout −5° C. to about −50° C. In some embodiments, apoptosis may beinduced using treatment temperatures from about −1° C. to about −15° C.,or from about −1° C. to about −19° C., optionally so as to provide alonger lasting treatment that limits or avoids inflammation andmobilization of skeletal muscle satellite repair cells. In someembodiments, axonotmesis with Wallerian degeneration of a sensory nerveis desired, which may be induced using treatment temperatures from about−20° C. to about −100° C. Hence, the duration of the treatment efficacyof such subdermal cryogenic treatments may be selected and controlled,with colder temperatures, longer treatment times, and/or larger volumesor selected patterns of target tissue determining the longevity of thetreatment. Additional description of cryogenic cooling methods anddevices may be found in commonly assigned U.S. Pat. No. 7,713,266 (Atty.Docket No. 000110US) entitled “Subdermal Cryogenic Remodeling of Muscle,Nerves, Connective Tissue, and/or Adipose Tissue (Fat)”, U.S. Pat. No.7,850,683 (Atty. Docket No. 000120US) entitled “Subdermal CryogenicRemodeling of Muscles, Nerves, Connective Tissue, and/or Adipose Tissue(Fat)”, U.S. patent application Ser. No. 13/325,004 (Atty. Docket No.002510US) entitled “Method for Reducing Hyperdynamic Facial Wrinkles”,and U.S. Pub. No. 2009/0248001 (Atty. Docket No. 000800US) entitled“Pain Management Using Cryogenic Remodeling,” the full disclosures ofwhich are each incorporated by reference herein.

Referring now to FIGS. 1A and 1B, a system for cryogenic remodeling herecomprises a self-contained probe handpiece generally having a proximalend 12 and a distal end 14. A handpiece body or housing 16 has a sizeand ergonomic shape suitable for being grasped and supported in asurgeon's hand or other system operator. As can be seen most clearly inFIG. 1B, a cryogenic cooling fluid supply 18, a supply valve 32 andelectrical power source 20 are found within housing 16, along with acircuit 22 having a processor for controlling cooling applied byself-contained system 10 in response to actuation of an input 24.Alternatively, electrical power can be applied through a cord from aremote power source. Power source 20 also supplies power to heaterelement 44 in order to heat the proximal region of probe 26 which maythereby help to prevent unwanted skin damage, and a temperature sensor48 adjacent the proximal region of probe 26 helps monitor probetemperature. Additional details on the heater 44 and temperature sensor48 are described in greater detail below. When actuated, supply valve 32controls the flow of cryogenic cooling fluid from fluid supply 18. Someembodiments may, at least in part, be manually activated, such asthrough the use of a manual supply valve and/or the like, so thatprocessors, electrical power supplies, and the like may not be required.

Extending distally from distal end 14 of housing 16 may be atissue-penetrating cryogenic cooling probe 26. Probe 26 is thermallycoupled to a cooling fluid path extending from cooling fluid source 18,with the exemplary probe comprising a tubular body receiving at least aportion of the cooling fluid from the cooling fluid source therein. Theexemplary probe 26 may comprise a 30 g needle having a sharpened distalend that is axially sealed. Probe 26 may have an axial length betweendistal end 14 of housing 16 and the distal end of the needle of betweenabout 0.5 mm and 15 cm, preferably having a length from about 3 mm toabout 10 mm. Such needles may comprise a stainless steel tube with aninner diameter of about 0.006 inches and an outer diameter of about0.012 inches, while alternative probes may comprise structures havingouter diameters (or other lateral cross-sectional dimensions) from about0.006 inches to about 0.100 inches. Generally, needle probe 26 maycomprise a 16 g or smaller size needle, often comprising a 20 g needleor smaller, typically comprising a 25, 26, 27, 28, 29, or 30 g orsmaller needle.

In some embodiments, probe 26 may comprise two or more needles arrangedin a linear array, such as those disclosed in previously incorporatedU.S. Pat. No. 7,850,683. Another exemplary embodiment of a probe havingmultiple needle probe configurations allow the cryogenic treatment to beapplied to a larger or more specific treatment area. Other needleconfigurations that facilitate controlling the depth of needlepenetration and insulated needle embodiments are disclosed in commonlyassigned U.S. Patent Publication No. 2008/0200910 (Atty. Docket No.000500US) entitled “Replaceable and/or Easily Removable Needle Systemsfor Dermal and Transdermal Cryogenic Remodeling,” the entire content ofwhich is incorporated herein by reference. Multiple needle arrays mayalso be arrayed in alternative configurations such as a triangular orsquare array.

Arrays may be designed to treat a particular region of tissue, or toprovide a uniform treatment within a particular region, or both. In someembodiments needle 26 may be releasably coupled with body 16 so that itmay be replaced after use with a sharper needle (as indicated by thedotted line) or with a needle having a different configuration. Inexemplary embodiments, the needle may be threaded into the body, pressfit into an aperture in the body or have a quick disconnect such as adetent mechanism for engaging the needle with the body. A quickdisconnect with a check valve may be advantageous since it may permitdecoupling of the needle from the body at any time without excessivecoolant discharge. This can be a useful safety feature in the event thatthe device fails in operation (e.g. valve failure), allowing an operatorto disengage the needle and device from a patient's tissue withoutexposing the patient to coolant as the system depressurizes. Thisfeature may also be advantageous because it allows an operator to easilyexchange a dull needle with a sharp needle in the middle of a treatment.One of skill in the art will appreciate that other coupling mechanismsmay be used.

Addressing some of the components within housing 16, the exemplarycooling fluid supply 18 may comprise a canister, sometimes referred toherein as a cartridge, containing a liquid under pressure, with theliquid preferably having a boiling temperature of less than 37° C. atone atmosphere of pressure. When the fluid is thermally coupled to thetissue-penetrating probe 26, and the probe is positioned within thepatient so that an outer surface of the probe is adjacent to a targettissue, the heat from the target tissue evaporates at least a portion ofthe liquid and the enthalpy of vaporization cools the target tissue. Asupply valve 32 may be disposed along the cooling fluid flow pathbetween canister 18 and probe 26, or along the cooling fluid path afterthe probe so as to limit coolant flow thereby regulating thetemperature, treatment time, rate of temperature change, or othercooling characteristics. The valve will often be powered electricallyvia power source 20, per the direction of processor 22, but may at leastin part be manually powered. The exemplary power source 20 comprises arechargeable or single-use battery. Additional details about valve 32are disclosed below and further disclosure on the power source 20 may befound in commonly assigned Int'l Pub. No. WO 2010/075438 (Atty. DocketNo. 002310PC) entitled “Integrated Cryosurgical Probe Package with FluidReservoir and Limited Electrical Power Source,” the entire contents ofwhich are incorporated herein by reference.

The exemplary cooling fluid supply 18 may comprise a single-usecanister. Advantageously, the canister and cooling fluid therein may bestored and/or used at (or even above) room temperature. The canister mayhave a frangible seal or may be refillable, with the exemplary canistercontaining liquid nitrous oxide, N₂O. A variety of alternative coolingfluids might also be used, with exemplary cooling fluids includingfluorocarbon refrigerants and/or carbon dioxide. The quantity of coolingfluid contained by canister 18 will typically be sufficient to treat atleast a significant region of a patient, but will often be less thansufficient to treat two or more patients. An exemplary liquid N₂Ocanister might contain, for example, a quantity in a range from about 1gram to about 40 grams of liquid, more preferably from about 1 gram toabout 35 grams of liquid, and even more preferably from about 7 grams toabout 30 grams of liquid.

Processor 22 will typically comprise a programmable electronicmicroprocessor embodying machine readable computer code or programminginstructions for implementing one or more of the treatment methodsdescribed herein. The microprocessor will typically include or becoupled to a memory (such as a non-volatile memory, a flash memory, aread-only memory (“ROM”), a random access memory (“RAM”), or the like)storing the computer code and data to be used thereby, and/or arecording media (including a magnetic recording media such as a harddisk, a floppy disk, or the like; or an optical recording media such asa CD or DVD) may be provided. Suitable interface devices (such asdigital-to-analog or analog-to-digital converters, or the like) andinput/output devices (such as USB or serial I/O ports, wirelesscommunication cards, graphical display cards, and the like) may also beprovided. A wide variety of commercially available or specializedprocessor structures may be used in different embodiments, and suitableprocessors may make use of a wide variety of combinations of hardwareand/or hardware/software combinations. For example, processor 22 may beintegrated on a single processor board and may run a single program ormay make use of a plurality of boards running a number of differentprogram modules in a wide variety of alternative distributed dataprocessing or code architectures.

Referring now to FIG. 2A, schematic 11 shows a simplified diagram ofcryogenic cooling fluid flow and control. The flow of cryogenic coolingfluid from fluid supply 18 may be controlled by a supply valve 32.Supply valve 32 may comprise an electrically actuated solenoid valve, amotor actuated valve or the like operating in response to controlsignals from controller 22, and/or may comprise a manual valve.Exemplary supply valves may comprise structures suitable for on/offvalve operation, and may provide venting of the fluid source and/or thecooling fluid path downstream of the valve when cooling flow is haltedso as to limit residual cryogenic fluid vaporization and cooling.Additionally, the valve may be actuated by the controller in order tomodulate coolant flow to provide high rates of cooling in some instanceswhere it is desirable to promote necrosis of tissue such as in malignantlesions and the like or slow cooling which promotes ice formationbetween cells rather than within cells when necrosis is not desired.More complex flow modulating valve structures might also be used inother embodiments. For example, other applicable valve embodiments aredisclosed in previously incorporated U.S. Pub. No. 2008/0200910.

Still referring to FIG. 2A, an optional heater (not illustrated) may beused to heat cooling fluid supply 18 so that heated cooling fluid flowsthrough valve 32 and through a lumen 34 of a cooling fluid supply tube36. In some embodiments a safety mechanism can be included so that thecooling supply is not overheated. Examples of such embodiments aredisclosed in commonly assigned International Publication No. WO2010075438, the entirety of which is incorporated by reference herein.

Supply tube 36 is, at least in part, disposed within a lumen 38 ofneedle 26, with the supply tube extending distally from a proximal end40 of the needle toward a distal end 42. The exemplary supply tube 36comprises a fused silica tubular structure (not illustrated) having apolymer coating and extending in cantilever into the needle lumen 38.Supply tube 36 may have an inner lumen with an effective inner diameterof less than about 200 μm, the inner diameter often being less thanabout 100 μm, and typically being less than about 40 μm. Exemplaryembodiments of supply tube 36 have inner lumens of between about 15 and50 μm, such as about 30 μm. An outer diameter or size of supply tube 36will typically be less than about 1000 μm, often being less than about800 μm, with exemplary embodiments being between about 60 and 150 μm,such as about 90 μm or 105 μm. The tolerance of the inner lumen diameterof supply tubing 36 will preferably be relatively tight, typically beingabout +/−10 μm or tighter, often being +/−5 μm or tighter, and ideallybeing +/−3 μm or tighter, as the small diameter supply tube may providethe majority of (or even substantially all of) the metering of thecooling fluid flow into needle 26. Additional details on various aspectsof needle 26 along with alternative embodiments and principles ofoperation are disclosed in greater detail in U.S. Patent Publication No.2008/0154254 (Atty. Docket No. 000300US) entitled “Dermal andTransdermal Cryogenic Microprobe Systems and Methods,” the entirecontents of which are incorporated herein by reference. Previouslyincorporated U.S. Patent Publication No. 2008/0200910 (Attorney DocketNo. 025917-000500US) also discloses additional details on the needle 26along with various alternative embodiments and principles of operation.

The cooling fluid injected into lumen 38 of needle 26 will typicallycomprise liquid, though some gas may also be injected. At least some ofthe liquid vaporizes within needle 26, and the enthalpy of vaporizationcools the needle and also the surrounding tissue engaged by the needle.An optional heater 44 (illustrated in FIG. 1B) may be used to heat theproximal region of the needle in order to prevent unwanted skin damagein this area, as discussed in greater detail below. Controlling apressure of the gas/liquid mixture within needle 26 substantiallycontrols the temperature within lumen 38, and hence the treatmenttemperature range of the tissue. A relatively simple mechanical pressurerelief valve 46 may be used to control the pressure within the lumen ofthe needle, with the exemplary valve comprising a valve body such as aball bearing, urged against a valve seat by a biasing spring. Anexemplary relief valve is disclosed in U.S. Provisional PatentApplication No. 61/116,050 previously incorporated herein by reference.Thus, the relief valve may allow better temperature control in theneedle, minimizing transient temperatures. Further details on exhaustvolume are disclosed in previously incorporated U.S. Pat. Pub. No.2008/0200910.

The heater 44 may be thermally coupled to a thermally responsive element50, which is supplied with power by the controller 22 and thermallycoupled to a proximal portion of the needle 26. The thermally responsiveelement 50 can be a block constructed from a material of high thermalconductivity and low heat capacity, such as aluminum. A firsttemperature sensor 52 (e.g., thermistor, thermocouple) can also bethermally coupled the thermally responsive element 50 andcommunicatively coupled to the controller 22. A second temperaturesensor 53 can also be positioned near the heater 44, for example, suchthat the first temperature sensor 52 and second temperature sensor 53are placed in different positions within the thermally responsiveelement 50. In some embodiments, the second temperature sensor 53 isplaced closer to a tissue contacting surface than the first temperaturesensor 52 is placed in order to provide comparative data (e.g.,temperature differential) between the sensors 52, 53. The controller 22can be configured to receive temperature information of the thermallyresponsive element 50 via the temperature sensor 52 in order to providethe heater 44 with enough power to maintain the thermally responsiveelement 50 at a particular temperature.

The controller 22 can be further configured to monitor power draw fromthe heater 44 in order to characterize tissue type, perform devicediagnostics, and/or provide feedback for a tissue treatment algorithm.This can be advantageous over monitoring temperature alone, since powerdraw from the heater 44 can vary greatly while temperature of thethermally responsive element 50 remains relatively stable. For example,during treatment of target tissue, maintaining the thermally responsiveelement 50 at 40° C. during a cooling cycle may take 1.0 W initially(for a needle <10 mm in length) and is normally expected to climb to 1.5W after 20 seconds, due to the needle 26 drawing in surrounding heat. Anindication that the heater is drawing 2.0 W after 20 seconds to maintain40° C. can indicate that an aspect of the system 10 is malfunctioningand/or that the needle 26 is incorrectly positioned. Correlations withpower draw and correlated device and/or tissue conditions can bedetermined experimentally to determine acceptable treatment powerranges.

In some embodiments, it may be preferable to limit frozen tissue that isnot at the treatment temperature, i.e., to limit the size of a formedcooling zone within tissue. Such cooling zones may be associated with aparticular physical reaction, such as the formation of an ice-ball, orwith a particular temperature profile or temperature volume gradientrequired to therapeutically affect the tissue therein. To achieve this,metering coolant flow could maintain a large thermal gradient at itsoutside edges. This may be particularly advantageous in applications forcreating an array of connected cooling zones (i.e., fence) in atreatment zone, as time would be provided for the treatment zone tofully develop within the fenced in portion of the tissue, while theouter boundaries maintained a relatively large thermal gradient due tothe repeated application and removal of refrigeration power. This couldprovide a mechanism within the body of tissue to thermally regulate thetreatment zone and could provide increased ability to modulate thetreatment zone at a prescribed distance from the surface of the skin. Arelated treatment algorithm could be predefined, or it could be inresponse to feedback from the tissue.

Such feedback could be temperature measurements from the needle 26, orthe temperature of the surface of the skin could be measured. However,in many cases monitoring temperature at the needle 26 is impractical dueto size constraints. To overcome this, operating performance of thesensorless needle 26 can be interpolated by measuring characteristics ofthermally coupled elements, such as the thermally responsive element 50.

Additional methods of monitoring cooling and maintaining an unfrozenportion of the needle include the addition of a heating element and/ormonitoring element into the needle itself. This could consist of a smallthermistor or thermocouple, and a wire that could provide resistiveheat. Other power sources could also be applied such as infrared light,radiofrequency heat, and ultrasound. These systems could also be appliedtogether dependent upon the control of the treatment zone desired.

Alternative methods to inhibit excessively low transient temperatures atthe beginning of a refrigeration cycle might be employed instead of ortogether with the limiting of the exhaust volume. For example, thesupply valve 32 might be cycled on and off, typically by controller 22,with a timing sequence that would limit the cooling fluid flowing sothat only vaporized gas reached the needle lumen 38 (or a sufficientlylimited amount of liquid to avoid excessive dropping of the needle lumentemperature). This cycling might be ended once the exhaust volumepressure was sufficient so that the refrigeration temperature would bewithin desired limits during steady state flow. Analytical models thatmay be used to estimate cooling flows are described in greater detail inpreviously incorporated U.S. Patent Pub. No. 2008/0154254.

FIG. 2B shows a cross-section of the housing 16. This embodiment of thehousing 16 may be powered by an external source, hence the attachedcable, but could alternatively include a portable power source. Asshown, the housing includes a cartridge holder 50. The cartridge holder50 includes a cartridge receiver 52, which may be configured to hold apressured refrigerant cartridge 18. The cartridge receiver 52 includesan elongated cylindrical passage 54, which is dimensioned to hold acommercially available cooling fluid cartridge 18. A distal portion ofthe cartridge receiver 52 includes a filter device 56, which has anelongated conical shape. In some embodiments, the cartridge holder 50may be largely integrated into the housing 16 as shown, however, inalternative embodiments, the cartridge holder 50 is a wholly separateassembly, which may be pre-provided with a coolant fluid source 18.

The filter device 56 may fluidly couple the coolant fluid source(cartridge) 18 at a proximal end to the valve 32 at a distal end. Thefilter device 56 may include at least one particulate filter 58. In theshown embodiment, a particulate filter 58 at each proximal and distalend of the filter device 56 may be included. The particulate filter 58can be configured to prevent particles of a certain size from passingthrough. For example, the particulate filter 58 can be constructed as amicroscreen having a plurality of passages less than 2 microns in width,and thus particles greater than 2 microns would not be able to pass.

The filter device 56 also includes a molecular filter 60 that isconfigured to capture fluid impurities. In some embodiments, themolecular filter 60 is a plurality of filter media (e.g., pellets,powder, particles) configured to trap molecules of a certain size. Forexample, the filter media can comprise molecular sieves having poresranging from 1-20 Å. In another example, the pores have an average sizeof 5 Å. The molecular filter 60 can have two modalities. In a firstmode, the molecular filter 60 will filter fluid impurities received fromthe cartridge 18. However, in another mode, the molecular filter 60 cancapture impurities within the valve 32 and fluid supply tube 36 when thesystem 10 is not in use, i.e., when the cartridge 18 is not fluidlyconnected to the valve 32.

Alternatively, the filter device 56 can be constructed primarily fromePTFE (such as a GORE material), sintered polyethylene (such as made byPOREX), or metal mesh. The pore size and filter thickness can beoptimized to minimize pressure drop while capturing the majority ofcontaminants. These various materials can be treated to make ithydrophobic (e.g., by a plasma treatment) and/or oleophobic so as torepel water or hydrocarbon contaminants.

It has been found that in some instances fluid impurities may leach outfrom various aspects of the system 10. These impurities can includetrapped moisture in the form of water molecules and chemical gasses. Thepresence of these impurities is believed to hamper cooling performanceof the system 10. The filter device 56 can act as a desiccant thatattracts and traps moisture within the system 10, as well as chemicalsout gassed from various aspects of the system 10. Alternately thevarious aspects of the system 10 can be coated or plated withimpermeable materials such as a metal.

As shown in FIG. 2B and in more detail in FIG. 2C and FIG. 2D, thecartridge 18 can be held by the cartridge receiver 52 such that thecartridge 18 remains intact and unpunctured. In this inactive mode, thecartridge may not be fluidly connected to the valve 32. A removablecartridge cover 62 can be attached to the cartridge receiver 52 suchthat the inactive mode is maintained while the cartridge is held by thesystem 10.

In use, the cartridge cover 62 can be removed and supplied with acartridge containing a cooling fluid. The cartridge cover 62 can then bereattached to the cartridge receiver 52 by turning the cartridge cover62 until female threads 64 of the cartridge cover 62 engage with malethreads of the cartridge receiver 52. The cartridge cover 62 can beturned until resilient force is felt from an elastic seal 66, as shownin FIG. 2C. To place the system 10 into use, the cartridge cover 62 canbe further turned until the distal tip of the cartridge 18 is puncturedby a puncture pin connector 68, as shown in FIG. 2D. Once the cartridge18 is punctured, cooling fluid may escape the cartridge by flowingthrough the filter device 56, where the impurities within the coolingfluid may be captured. The purified cooling fluid then passes to thevalve 32, and onto the coolant supply tube 36 to cool the probe 26. Insome embodiments the filter device, or portions thereof, may bereplaceable.

In some embodiments, the puncture pin connector 68 can have a two-wayvalve (e.g., ball/seat and spring) that is closed unless connected tothe cartridge. Alternately, pressure can be used to open the valve. Thevalve closes when the cartridge is removed. In some embodiments, theremay be a relief valve piloted by a spring which is balanced byhigh-pressure nitrous when the cartridge is installed and the system ispressurized, but allows the high-pressure cryogen to vent when thecryogen is removed. In addition, the design can include a vent port thatvents cold cryogen away from the cartridge port. Cold venting cryogenlocally can cause condensation in the form of liquid water to form fromthe surrounding environment. Liquid water or water vapor entering thesystem can hamper the cryogenic performance. Further, fluid carryingportions of the cartridge receiver 52 can be treated (e.g., plasmatreatment) to become hydrophobic and/or oleophobic so as to repel wateror hydrocarbon contaminants.

Turning now to FIG. 3A and FIG. 3B, an exemplary embodiment of probe 300having multiple needles 302 is described. In FIG. 3A, probe housing 316includes threads 306 that allow the probe to be threadably engaged withthe housing 16 of a cryogenic device. O-rings 308 fluidly seal the probehousing 316 with the device housing 16 and prevent coolant from leakingaround the interface between the two components. Probe 300 includes anarray of three distally extending needle shafts 302, each having asharpened, tissue penetrating tip 304. Using three linearly arrangedneedles allows a greater area of tissue to be treated as compared with asingle needle. In use, coolant flows through lumens 310 into the needleshafts 302 thereby cooling the needle shafts 302. Ideally, only thedistal portion of the needle shaft 302 would be cooled so that only thetarget tissue receives the cryogenic treatment. However, as the coolingfluid flows through the probe 300, probe temperature decreasesproximally along the length of the needle shafts 302 towards the probehub 318. The proximal portion of needle shaft 302 and the probe hub 318contact skin and may become very cold (e.g. −20° C. to −25° C.) and thiscan damage the skin in the form of blistering or loss of skinpigmentation. Therefore it would be desirable to ensure that theproximal portion of needle shaft 302 and hub 318 remains warmer than thedistal portion of needle shaft 302. A proposed solution to thischallenge is to include a heater element 314 that can heat the proximalportion of needle shaft 302 and an optional temperature sensor 312 tomonitor temperature in this region. To further this, a proximal portionof the needle shaft 302 can be coated with a highly thermally conductivematerial, e.g., gold, that is conductively coupled to both the needleshaft 302 and heater element 314. Details of this construction aredisclosed below.

In the exemplary embodiment of FIG. 3A, resistive heater element 314 isdisposed near the needle hub 318 and near a proximal region of needleshaft 302. The resistance of the heater element is preferably 1Ω to 1KΩ, and more preferably from 5Ω to 50Ω. Additionally, a temperaturesensor 312 such as a thermistor or thermocouple is also disposed in thesame vicinity. Thus, during a treatment as the needles cool down, theheater 314 may be turned on in order to heat the hub 318 and proximalregion of needle shaft 302, thereby preventing this portion of thedevice from cooling down as much as the remainder of the needle shaft302. The temperature sensor 312 may provide feedback to controller 22and a feedback loop can be used to control the heater 314. The coolingpower of the nitrous oxide may eventually overcome the effects of theheater, therefore the microprocessor may also be programmed with awarning light and/or an automatic shutoff time to stop the coolingtreatment before skin damage occurs. An added benefit of using such aheater element is the fact that the heat helps to moderate the flow ofcooling fluid into the needle shaft 302 helping to provide more uniformcoolant mass flow to the needles shaft 302 with more uniform coolingresulting.

The embodiment of FIG. 3A illustrates a heater fixed to the probe hub.In other embodiments, the heater may float, thereby ensuring proper skincontact and proper heat transfer to the skin. Examples of floatingheaters are disclosed in commonly assigned Int'l Pub. No. WO 2010/075448(Atty. Docket No. 002310PC) entitled “Skin Protection for SubdermalCryogenic Remodeling for Cosmetic and Other Treatments,” the entirety ofwhich is incorporated by reference herein.

In this exemplary embodiment, three needles are illustrated. One ofskill in the art will appreciate that a single needle may be used, aswell as two, four, five, six, or more needles may be used. When aplurality of needles are used, they may be arranged in any number ofpatterns. For example, a single linear array may be used, or a twodimensional or three dimensional array may be used. Examples of twodimensional arrays include any number of rows and columns of needles(e.g. a rectangular array, a square array, elliptical, circular,triangular, etc.), and examples of three dimensional arrays includethose where the needle tips are at different distances from the probehub, such as in an inverted pyramid shape.

FIG. 3B illustrates a cross-section of the needle shaft 302 of needleprobe 300. The needle shaft can be conductively coupled (e.g., welded,conductively bonded, press fit) to a conductive heater 314 to enableheat transfer therebetween. The needle shaft 302 is generally a small(e.g., 20-30 gauge) closed tip hollow needle, which can be between about0.2 mm and 15 cm, preferably having a length from about 0.3 cm to about1.5 cm. The conductive heater element 314 can be housed within aconductive block 315 of high thermally conductive material, such asaluminum and include an electrically insulated coating, such as Type IIIanodized coating to electrically insulate it without diminishing itsheat transfer properties. The conductive block 315 can be heated by aresister or other heating element (e.g. cartridge heater, nichrome wire,etc.) bonded thereto with a heat conductive adhesive, such as epoxy. Athermistor can be coupled to the conductive block 315 with heatconductive epoxy allows temperature monitoring. Other temperaturesensors may also be used, such as a thermocouple.

A cladding 320 of conductive material is directly conductively coupledto the proximal portion of the shaft of the needle 302, which can bestainless steel. In some embodiments, the cladding 320 is a layer ofgold, or alloys thereof, coated on the exterior of the proximal portionof the needle shaft 302. In some embodiments, the exposed length ofcladding 320 on the proximal portion of the needle is 2-100 mm. In someembodiments, the cladding 320 can be of a thickness such that the cladportion has a diameter ranging from 0.017-0.020 in., and in someembodiments 0.0182 in. Accordingly, the cladding 320 can be conductivelycoupled to the material of the needle 302, which can be less conductive,than the cladding 320. The cladding 320 may modify the lateral forcerequired to deflect or bend the needle 26. Cladding 320 may be used toprovide a stiffer needle shaft along the proximal end in order to moreeasily transfer force to the leading tip during placement and allow thedistal portion of the needle to deflect more easily when it isdissecting a tissue interface within the body. The stiffness of needle26 can vary from one end to the other end by other means such asmaterial selection, metal tempering, variation of the inner diameter ofthe needle 26, or segments of needle shaft joined together end-to-end toform one contiguous needle 26. In some embodiments, increasing thestiffness of the distal portion of the needle 26 can be used to flex theproximal portion of the needle to access difficult treatment sites as inthe case of upper limb spasticity where bending of the needle outsidethe body may be used to access a target peripheral nerve along thedesired tissue plane.

In some embodiments, the cladding 320 can include sub-coatings (e.g.,nickel) that promote adhesion of an outer coating that would otherwisenot bond well to the needle shaft 302. Other highly conductive materialscan be used as well, such as copper, silver, aluminum, and alloysthereof In some embodiments, a protective polymer or metal coating cancover the cladding to promote biocompatibility of an otherwisenon-biocompatible but highly conductive cladding material. Such abiocompatible coating however, would be applied to not disruptconductivity between the conductive block 315. In some embodiments, aninsulating layer, such as a ceramic material, is coated over thecladding 320, which remains conductively coupled to the needle shaft302.

In use, the cladding 320 can transfer heat to the proximal portion ofthe needle 302 to prevent directly surrounding tissue from dropping tocryogenic temperatures. Protection can be derived from heating thenon-targeting tissue during a cooling procedure, and in some embodimentsbefore the procedure as well. The mechanism of protection may beproviding heat to pressurized cryogenic cooling fluid passing within theproximal portion of the needle to affect complete vaporization of thefluid. Thus, the non-target tissue in contact with the proximal portionof the needle shaft 302 does not need to supply heat, as opposed totarget tissue in contact with the distal region of the needle shaft 302.To help further this effect, in some embodiments the cladding 320 iscoating within the interior of the distal portion of the needle, with orwithout an exterior cladding. To additionally help further this effect,in some embodiments, the distal portion of the needle can be thermallyisolated from the proximal portion by a junction, such as a ceramicjunction. While in some further embodiments, the entirety of theproximal portion is constructed from a more conductive material than thedistal portion.

In use, it has been determined experimentally that the cladding 320 canhelp limit formation of a cooling zone to the distal portion of theneedle shaft 302, which tends to demarcate at a distal end of thecladding 320. Accordingly, cooling zones are formed only about thedistal portions of the needles. Thus, non-target tissue in directcontact with proximal needle shafts remain protected from effects ofcryogenic temperatures. Such effects can include discoloration andblistering of the skin. Such cooling zones may be associated with aparticular physical reaction, such as the formation of an ice-ball, orwith a particular temperature required to therapeutically affect thetissue therein.

Standard stainless steel needles and gold clad steel needles were testedin porcine muscle and fat. Temperatures were recorded measured 2 mm fromthe proximal end of the needle shafts, about where the cladding distallyterminates, and at the distal tip of the needles. Temperatures for cladneedles were dramatically warmer at the 2 mm point versus the uncladneedles, and did not drop below 4° C. The 2 mm points of the standardstainless steel needles almost equalize in temperature with the distaltip at temperatures below 0° C.

FIGS. 3C and 3D illustrates a detachable probe tip 322 having a hubconnector 324 and an elongated probe 326. The probe tip 322 shares muchof its construction with probe 300. However, the elongated probe 326features a blunt tip 328 that is adapted for blunt dissection of tissue.The blunt tip 328 can feature a full radius tip, less than a full radiustip, or conical tip. In some embodiments, a dulled or truncated needleis used. The elongated probe 326 can be greater than 20 gauge in size,and in some embodiments range in size from 25-30 gauge. As with theembodiments described above, an internal supply tube 330 extends incantilever. However, the exit of the supply tube 330 can be disposed atpositions within the elongated probe 326 other than proximate the blunttip 328. Further, the supply tube 330 can be adapted to create anelongated zone of cooling, e.g., by having multiple exit points forcryofluid to exit from.

The elongated probe 326 and supply tube 330 may be configured toresiliently bend in use, throughout their length at angles approaching120°, with a 5-10 mm bend radius. This may be very challengingconsidering the small sizes of the elongated probe 326 and supply tube330, and also considering that the supply tube 330 is often constructedfrom fused silica. Accordingly, the elongated probe 326 can beconstructed from a resilient material, such as stainless steel, and of aparticular diameter and wall thickness [0.004 to 1.0 mm], such that theelongated probe in combination with the supply tube 330 is not overlyresilient so as to overtly resist manipulation, but sufficiently strongso as to prevent kinking that can result in coolant escaping. Forexample, the elongated probe can be 15 gauge or smaller in diameter,even ranging from 20-30 gauge in diameter. The elongated probe can havea very disparate length to diameter ratio, for example, the elongatedprobe can be greater than 30 mm in length, and in some cases range from30-100 mm in length. To further the aforementioned goals, the supplytube 330 can include a polymer coating 332, such as a polyimide coatingthat terminates approximately halfway down its length, to resist kinkingand aid in resiliency. The polymer coating 332 can be a secondarycoating over a primary polyimide coating that extends fully along thesupply tube. However, it should be understood that the coating is notlimited to polyimide, and other suitable materials can be used. In someembodiments, the flexibility of the elongated probe 326 will vary fromthe proximal end to the distal end. For example, by creating certainportions that have more or less flexibility than others. This may bedone, for example, by modifying wall thickness, adding material (such asthe cladding discussed above), and/or heat treating certain portions ofthe elongated probe 326 and/or supply tube 330. For example, decreasingthe flexibility of elongated probe 326 along the proximal end canimprove the transfer of force from the hand piece to the elongated probeend for better feel and easier tip placement for treatment. Theelongated probe and supply line 330 are may be configured to resilientlybend in use to different degrees along the length at angles approaching120°, with a varying bend radius as small as 5 mm. In some embodiments,the elongated probe 326 will have external markings along the needleshaft indicating the length of needle inserted into the tissue.

FIG. 3E illustrates an exemplary detachable probe tip 322 insertedthrough skin surface SS. As illustrated, the probe tip 322 is insertedalong an insertion axis IA through the skin surface SS. Thereafter, theneedle may be bent away from the insertion axis IA and advanced toward atarget tissue TT in order to position blunt tip 328 adjacent to thetarget tissue TT. In some embodiments, the target tissue may be theinfrapatellar branch of the saphenous nerve. In other embodiments thetarget tissue may be one or more branches of the anterior femoralcutaneous nerve or the lateral femoral cutaneous nerve.

In some embodiments, the probe tip 322 does not include a heatingelement, such as the heater described with reference to probe 300, sincethe effective treating portion of the elongated probe 326 (i.e., thearea of the elongated probe where a cooling zone emanates from) is welllaterally displaced from the hub connector 324 and elongated probeproximal junction. Embodiments of the supply tube are further describedbelow and within commonly assigned U.S. Pub. No. 2012/0089211, which isincorporated by reference.

FIGS. 4A-4C illustrate an exemplary method of creating a hole throughthe skin that allows multiple insertions and positioning of a cryoprobetherethrough. In FIG. 4A a cannula or sheath 1902 is disposed over aneedle 1904 having a tissue penetrating distal end 1908. The cannula mayhave a tapered distal portion 1906 to help spread and dilate the skinduring insertion. The needle/sheath assembly is then advanced into andpierces the skin 1910 into the desired target tissue 1912. The innerpathway of the cannula or sheath 1902 may be curved to assist indirecting the flexible needle 1904, or other probe, into a desiredtissue layer coincident with the desired needle path in the tissue. Oncethe needle/sheath assembly has been advanced to a desired location, theneedle 1904 may be proximally retracted and removed from the sheath1902. The sheath now may be used as an easy way of introducing acryoprobe through the skin without piercing it, and directing thecryoprobe to the desired target treatment area. FIG. 4B shows the sheath1902 in position with the needle 1904 removed. FIG. 4C shows insertionof a cryoprobe 1914 into the sheath such that a blunt tip 1916 of thecryoprobe 1914 is adjacent the target treatment tissue. The cryoprobemay then be cooled and the treatment tissue cooled to achieve any of thecosmetic or therapeutic effects discussed above. In this embodiment, thecryoprobe preferably has a blunt tip 1916 in order to minimize tissuetrauma. In other embodiments, the tip may be sharp and be adapted topenetrate tissue, or it may be round and spherical. The cryoprobe 1914may then be at least partially retracted from the sheath 1902 and/orrotated and then re-advanced to the same or different depth andrepositioned in sheath 1902 so that the tip engages a different portionof the target treatment tissue without requiring an additional piercingof the skin. The probe angle relative to the tissue may also beadjusted, and the cryoprobe may be advanced and retracted multiple timesthrough the sheath so that the entire target tissue is cryogenicallytreated.

While the embodiment of FIGS. 4A-4C illustrates a cryoprobe having onlya single probe, the cryoprobe may have an array of probes. Any of thecryoprobes described above may be used with an appropriately sizedsheath. In some embodiments, the cryoprobe comprises a linear or twodimensional array of probes. Lidocaine or other local anesthetics may beused during insertion of the sheath or cryoprobe in order to minimizepatient discomfort. The angle of insertion for the sheath may beanywhere from 0 to 180 degrees relative to the skin surface, and inspecific embodiments is 15 to 45 degrees. The sheath may be inserted atany depth, but in specific embodiments of treating lines/wrinkles of theface, the sheath may be inserted to a depth of 1 mm to 10 mm, and morepreferably to a depth of 2 mm to 5 mm.

In an alternative embodiment seen in FIG. 4D, the sheath 1902 mayinclude an annular flange 1902 b on an outside surface of the sheath inorder to serve as a stop so that the sheath is only inserted a presetamount into the tissue. The position of the flange 1902 b may beadjustable or fixed. The proximal end of the sheath in this embodiment,or any of the other sheath embodiments may also include a one way valvesuch as a hemostasis valve to prevent backflow of blood or other fluidsthat may exit the sheath. The sheath may also insulate a portion of thecryoprobe and prevent or minimize cooling of unwanted regions of tissue.

Any of the cryoprobes described above may be used with the sheathembodiment described above (e.g. in FIGS. 3B, 4A-4C). Other cryoprobesmay also be used with this sheath embodiment, or they may be used alone,in multi-probe arrays, or combined with other treatments. For example, aportion of the cryoprobe 2006 may be insulated as seen in FIG. 5.Cryoprobe 2006 includes a blunt tip 2004 with an insulated section 2008of the probe. Thus, when the cryoprobe is disposed in the treatmenttissue under the skin 2002 and cooled, the cryoprobe preferentiallycreates a cooling zone along one side while the other side remainsuncooled, or only experiences limited cooling. For example, in FIG. 5,the cooling zone 2010 is limited to a region below the cryoprobe 2006,while the region above the cryoprobe and below the skin 2002 remainunaffected by the cooling.

Different zones of cryotherapy may also be created by differentgeometries of the coolant fluid supply tube that is disposed in thecryoprobe. FIGS. 6-9 illustrate exemplary embodiments of differentcoolant fluid supply tubes. In FIG. 6 the coolant fluid supply tube 2106is offset from the central axis of a cryoprobe 2102 having a blunt tip2104. Additionally, the coolant fluid supply tube 2106 includes severalexit ports for the coolant including circular ports 2110, 2112 near thedistal end of the coolant fluid supply tube and an elliptical port 2108proximal of the other ports. These ports may be arranged in varyingsizes, and varying geometries in order to control the flow of cryofluidwhich in turn controls probe cooling of the target tissue. FIG. 7illustrates an alternative embodiment of a coolant fluid supply tube2202 having a plurality of circular ports 2204 for controlling cryofluidflow. FIG. 8 illustrates yet another embodiment of a coolant fluidsupply tube 2302 having a plurality of elliptical holes 2304, and FIG. 9shows still another embodiment of a coolant fluid supply tube 2402having a plurality of ports ranging from smaller diameter circular holes2404 near the distal end of the supply tube 2402 to larger diametercircular holes 2406 that are more proximally located on the supply tube2402.

As discussed above, it may be preferable to have a blunt tip on thedistal end of the cryoprobe in order to minimize tissue trauma. Theblunt tip may be formed by rounding off the distal end of the probe, ora bladder or balloon 2506 may be placed on the distal portion of theprobe 2504 as seen in FIG. 10. A filling tube or inflation lumen 2502may be integral with or separate from the cryoprobe 2504, and may beused to deliver fluid to the balloon to fill the balloon 2506 up to formthe atraumatic tip.

In some instances, it may be desirable to provide expandable cryoprobesthat can treat different target tissues or accommodate differentanatomies. For example, in FIGS. 11 and 12, a pair of cryoprobes 2606with blunt tips 2604 may be delivered in parallel with one another andin a low profile through a sheath 2602 to the treatment area. Oncedelivered, the probes may be actuated to separate the tips 2604 from oneanother, thereby increasing the cooling zone. After the cryotherapy hasbeen administered, the probes may be collapsed back into their lowprofile configuration, and retracted from the sheath.

In some embodiments, the probe may have a sharp tissue piercing distaltip, and in other embodiments, the probe may have a blunt tip forminimizing tissue trauma. To navigate through tissue, it may bedesirable to have a certain column strength for the probe in order toavoid bending, buckling or splaying, especially when the probe comprisestwo or more probes in an array. One exemplary embodiment may utilize avariable stiff portion of a sleeve along the probe body to provideadditional column strength for pushing the probe through tissue.

An exemplary algorithm 400 for controlling the heater element 314, andthus for transferring heat to the cladding 320, is illustrated in FIG.13. In FIG. 13, the start of the interrupt service routine (ISR) 402begins with reading the current needle hub temperature 404 using atemperature sensor such as a thermistor or thermocouple disposed nearthe needle hub. The time of the measurement is also recorded. This datais fed back to controller 22 where the slope of a line connecting twopoints is calculated. The first point in the line is defined by thecurrent needle hub temperature and time of its measurement and thesecond point consists of a previous needle hub temperature measurementand its time of measurement. Once the slope of the needle hubtemperature curve has been calculated 406, it is also stored 408 alongwith the time and temperature data. The needle hub temperature slope isthen compared with a slope threshold value 410. If the needle hubtemperature slope is less than the threshold value then a treating flagis activated 412 and the treatment start time is noted and stored 414.If the needle hub slope is greater than or equal to the slope thresholdvalue 410, an optional secondary check 416 may be used to verify thatcooling has not been initiated. In step 416, absolute needle hubtemperature is compared to a temperature threshold. If the hubtemperature is less than the temperature threshold, then the treatingflag is activated 412 and the treatment start time is recorded 414 aspreviously described. As an alternative, the shape of the slope could becompared to a norm, and an error flag could be activated for an out ofnorm condition. Such a condition could indicate the system was notheating or cooling sufficiently. The error flag could trigger anautomatic stop to the treatment with an error indicator light.Identifying the potential error condition and possibly stopping thetreatment may prevent damage to the proximal tissue in the form of toomuch heat, or too much cooling to the tissue. The algorithm preferablyuses the slope comparison as the trigger to activate the treatment flagbecause it is more sensitive to cooling conditions when the cryogenicdevice is being used rather than simply measuring absolute temperature.For example, a needle probe exposed to a cold environment wouldgradually cool the needle down and this could trigger the heater to turnon even though no cryogenic cooling treatment was being conducted. Theslope more accurately captures rapid decreases in needle temperature asare typically seen during cryogenic treatments.

When the treatment flag is activated 418 the needle heater is enabled420 and heater power may be adjusted based on the elapsed treatment timeand current needle hub temperature 422. Thus, if more heat is required,power is increased and if less heat is required, power is decreased.Whether the treatment flag is activated or not, as an additional safetymechanism, treatment duration may be used to control the heater element424. As mentioned above, eventually, cryogenic cooling of the needlewill overcome the effects of the heater element. In that case, it wouldbe desirable to discontinue the cooling treatment so that the proximalregion of the probe does not become too cold and cause skin damage.Therefore, treatment duration is compared to a duration threshold valuein step 424. If treatment duration exceeds the duration threshold thenthe treatment flag is cleared or deactivated 426 and the needle heateris deactivated 428. If the duration has not exceeded the durationthreshold 424 then the interrupt service routine ends 430. The algorithmthen begins again from the start step 402. This process continues aslong as the cryogenic device is turned on.

Preferred ranges for the slope threshold value may range from about −5°C. per second to about −90° C. per second and more preferably range fromabout −30° C. per second to about −57° C. per second. Preferred rangesfor the temperature threshold value may range from about 15° C. to about0° C., and more preferably may range from about 0° C. to about 10° C.Treatment duration threshold may range from about 15 seconds to about 75seconds.

It should be appreciated that the specific steps illustrated in FIG. 13provide a particular method of heating a cryogenic probe, according toan embodiment of the present invention. Other sequences of steps mayalso be performed according to alternative embodiments. For example,alternative embodiments of the present invention may perform the stepsoutlined above in a different order. Moreover, the individual stepsillustrated in FIG. 13 may include multiple sub-steps that may beperformed in various sequences as appropriate to the individual step.Furthermore, additional steps may be added or removed depending on theparticular applications.

The heating algorithm may be combined with a method for treating apatient. Referring now to FIG. 14, a method 100 facilitates treating apatient using a cryogenic cooling system having a reusable or disposablehandpiece either of which that can be self-contained or externallypowered with replaceable needles such as those of FIG. 1B and a limitedcapacity battery or metered electrical supply. Method 100 generallybegins with a determination 110 of the desired tissue therapy andresults, such as the inhibition of pain from a particular site.Appropriate target tissues for treatment are identified 112 (a tissuethat transmits the pain signal), allowing a target treatment depth,target treatment temperature profile, or the like to be determined. Step112 may include performing a tissue characterization and/or devicediagnostic algorithm, based on power draw of system 10, for example.

The application of the treatment algorithm 114 may include the controlof multiple parameters such as temperature, time, cycling, pulsing, andramp rates for cooling or thawing of treatment areas. In parallel withthe treatment algorithm 114, one or more power monitoring algorithms 115can be implemented. An appropriate needle assembly can then be mounted116 to the handpiece, with the needle assembly optionally having aneedle length, skin surface cooling chamber, needle array, and/or othercomponents suitable for treatment of the target tissues. Simpler systemsmay include only a single needle type, and/or a first needle assemblymounted to the handpiece.

Pressure, heating, cooling, or combinations thereof may be applied 118to the skin surface adjacent the needle insertion site before, during,and/or after insertion 120 and cryogenic cooling 122 of the needle andassociated target tissue. Non-target tissue directly above the targettissue can be protected by directly conducting energy in the form ofheat to the cladding on a proximal portion of the needle shaft duringcooling. Upon completion of the cryogenic cooling cycle the needles willneed additional “thaw” time 123 to thaw from the internally createdcooling zone to allow for safe removal of the probe without physicaldisruption of the target tissues, which may include, but not be limitedto nerves, muscles, blood vessels, or connective tissues. This thaw timecan either be timed with the refrigerant valve shut-off for as short atime as possible, preferably under 15 seconds, more preferably under 5seconds, manually or programmed into the controller to automaticallyshut-off the valve and then pause for a chosen time interval until thereis an audible or visual notification of treatment completion.

Heating of the needle may be used to prevent unwanted skin damage usingthe apparatus and methods previously described. The needle can then beretracted 124 from the target tissue. If the treatment is not complete126 and the needle is not yet dull 128, pressure and/or cooling can beapplied to the next needle insertion location site 118, and theadditional target tissue treated. However, as small gauge needles maydull after being inserted only a few times into the skin, any needlesthat are dulled (or otherwise determined to be sufficiently used towarrant replacement, regardless of whether it is after a singleinsertion, 5 insertions, or the like) during the treatment may bereplaced with a new needle 116 before the next application ofpressure/cooling 118, needle insertion 120, and/or the like. Once thetarget tissues have been completely treated, or once the cooling supplycanister included in the self-contained handpiece is depleted, the usedcanister and/or needles can be disposed of 130. The handpiece mayoptionally be discarded.

As noted above, suitable target tissues can be selected that include aparticular sensory nerve associated with pain, for example, such as:Myofascial, Fibromylagia, Lateral and Medial epicondylitis,Llio-hypo/llio-inguinal, Pudendal, Pyriformis, Osteo-Arthritis of theKnee, Patellar Tendonitis, Diabetic neuropathies, Carpal Tunnel, PhantomLimb, Migraine, Trigeminal Neuralgia, Occipital Neuralgia, ShoulderArthritis, Shoulder Tendonitis, Suprascapular, Failed Back, Sciatica,Facet, Herniated Disc, Sacoiliac, Sciatic, Morton's Neuroma, and PlantarFasciitis pain.

With respect to foot pain, sensory nerves of the foot may be targetedfor treatment according to embodiments of the present invention. In someembodiments of the invention, nerve entrapment (also known as a pinchednerve) causing pain in the foot of a patient may be treated by targetingthe associated sensory nerves of the foot with cooling treatment. Nerveentrapment may occur at various regions of the foot. A nerve entrapmentis frequently caused by trauma, such as pressure created by swelling,excess pressure from a tight shoe, or blunt trauma. Symptoms of nerveentrapment include shooting, burning pain or sensitivity on the topportion of the foot.

Further, in some embodiments, devices and methods are provided fortreatment of Morton's neuroma. Morton's neuroma is a disorder caused bydigital nerve entrapment under the intermetatarsal ligament and resultsin benign thickening of the nerve. This occurs most commonly at thesecond and third intermetatarsal spaces (i.e., between the third andfourth toes). Symptoms include burning or shooting pain in the areabetween the third and fourth toes, most often with walking. Anothercommon symptom is a vague feeling of pressure beneath the toes, as if asock was bunched-up underneath them. Morton's neuroma occurs morefrequently in women, possibly because of the frequency of narrow orhigh-heeled shoe wear. Advantageously, cryogenic cooling of the neuromamay treat that neuroma rather than simply blocking pain signals.Additionally, forefoot neuropathy associated with gout may be treated insome embodiments.

FIG. 15 illustrates the nerves of the lower leg and foot. The commonfibular (peroneal) nerve 600 branches off the sciatic nerve in thepopliteal region (behind the knee). It travels posterior to the head ofthe fibula to enter the lateral compartment of the leg. Here it dividesinto the superficial 602 and deep peroneal nerves 604.

The superficial peroneal nerve 602 runs through the lateral compartmentof the leg and innervates the muscles in the lateral compartment and theskin over the anterior portion of the ankle and the dorsum of the foot.The superficial peroneal nerve 602 branches into the medial andintermediate dorsal cutaneous nerves. FIG. 16 shows the branching of thesuperficial peroneal nerve 602 into the intermediate 610 and medialcutaneous nerves 612.

The deep peroneal nerve 604 runs through extensor digitorum longus anddown the interosseous membrane. It then crosses the tibia and enters thedorsum of the foot. The deep peroneal nerve 604 innervates the musclesin the anterior compartment of the leg and the dorsum of the foot. Italso supplies the skin between the first and second toes.

Sural nerve 606 is formed by the union of branches from both the tibialand peroneal nerve and runs between the heads of the gastrocnemius, butit runs under the lateral malleolus. The Sural nerve 606 innervates theskin on the lateral side of the leg and foot.

Saphenous nerve 608 is a branch of the femoral nerve and runs down themedial portion of the leg to the medial part of the foot and innervatesthe skin on the medial side of the ankle and foot.

FIGS. 17A-17B show further details of nerves located in the foot. Thetibial nerve 614 is a branch of the sciatic nerve. It runs down the leg,between the heads of the gastrocnemius, and passes under the soleus. Itcurves under the medial malleolus and continues into the foot. Itinnervates all the muscles in the posterior compartment of the leg. Inthe foot, it branches into the medial plantar nerve 616 and the lateralplantar nerve 618.

Medial plantar nerve 616 runs between the abductor halluces and flexordigitorum brevis in the foot. The medial plantar nerve 616 gives rightsto digital branches 620 which then give rise to common digital branches622 and finally, the terminal branches. This nerve 616 supplies the skinof the medial three and one-half digits. It innervates the skin on themedial side of the sole of the foot, and it is the nerve supply for someof the foot muscles. The medial plantar nerve 616 supplies the followingmuscles: abductor halluces, flexor digitorum brevis, flexor hallucesbrevis (in the third layer), and first lumbrical.

Lateral plantar nerve 618 runs between the quadratus plantae and flexordigitorum brevis. The lateral plantar nerve 618 gives rise to motorbranches, a deep branch 624 and finally branches to the skin of thelateral one and one-half digits. It innervates the skin on the lateralpart of the sole and several small muscles of the foot. The musclessupplied are the: abductor digiti minimi, accessory flexor (quadratusplantae), adductor halluces, flexor digiti minimi brevis, interossei,and lumbricals 3, 4, 5. Plantar digital nerves are nerves that branch ofthe medial and lateral plantar nerves 616, 618. Plantar digital nervesinnervate the skin and nail beds of the toes.

FIG. 18 shows innervation of the plantar aspect of the foot. The drawingillustrates the territories of the lateral calcaneal nerve (LCN), thelatereal plantar nerve (LPN), the medial calcaneal nerve (MCN), themedial plantar nerve (MPN), and the sural nerve (SN).

FIG. 19 shows the details of the intermediate dorsal cutaneous nerve610. The intermediate dorsal cutaneous nerve 610 is the term for theterminal/lateral branch of the peroneal nerve 602. The intermediatedorsal cutaneous nerve 610 is also called the external dorsal cutaneousbranch. The intermediate dorsal cutaneous nerve 610 supplies the dorsaldigital nerves and the foot dorsum to the toes (with the exception ofsections of the first and second toes). The intermediate dorsalcutaneous nerve 610 travels through the dorsum's lateral side and splitsinto digital branches. The dorsal branches supply the common borders ofthe third, fourth, and fifth toes. The nerve lies near the sural nerve606. The intermediate dorsal cutaneous nerve 616 sometimes communicateswith the sural nerve 606. The intermediate dorsal cutaneous nerve 616terminates near the terminal branches of the internal and externalplantar nerves.

The medial dorsal cutaneous nerve 612 is the term for theterminal/medial branch of the peroneal nerve 602. The medial dorsalcutaneous nerve is also called the internal dorsal cutaneous branch.This nerve 612 supplies the medial digital nerves and the foot dorsum tothe first, second, and third toes. The medial dorsal cutaneous nerve 612travels through the center of the dorsum and splits into digitalbranches. The dorsal branches supply the common borders of the first,second, and third toes. The branches of the medial dorsal cutaneousnerve 612 terminate near the terminal branches of the deep peronealnerve. The medial dorsal cutaneous nerve sometimes communicates with thedeep peroneal nerve. The medial dorsal cutaneous nerve terminates nearthe terminal branches of the internal plantar nerves.

FIG. 20 is a drawing of the dorsal aspect of the foot and illustratesthe territories of: the deep peroneal nerve (DPN), the lateral plantarnerve (LPN), the medial plantar nerve (MPN), the sural nerve (SN), andthe superficial peroneal nerve (SPN) via the medial and intermediatecutaneous nerves.

FIG. 21 shows an oblique coronal MR image. The MR image shows thesubcutaneous superficial peroneal nerve branches (arrowheads) and thegreat saphenous vein (arrow).

FIG. 22 shows a distal coronal MR image. The distal coronal MR imagedemonstrates the branches of the deep peroneal nerve (DPN) for the firstdorsal space (circled). The arrows indicate the second through thefourth dorsal spaces, and they also depict and the branches of thesuperficial peroneal nerve (SPN): the medial and intermediate cutaneousnerves.

FIG. 23 shows another distal coronal MR image. This distal coronal MRimage shows the termination along the first toe of the medial cutaneousnerve (thin arrow) and the medial plantar nerve (thick arrow).

The target nerve may be accessed, for example, by locating adjacentlandmarks and treating in a linear fashion to block the nerve at adesired location. In some embodiments, access to the target nerve may begained by either a dorsal approach or plantar approach. In some cases itis advantageous treat an area proximal along the nerve from the neuromaor area of focused pain to extend the duration of treatment.

Studies were conducted to determine cryogenic cooling's effect onreducing forefoot pain. This prospective, non-randomized, interventionalstudy enrolled seven Subjects with a diagnosis of forefoot pain relatedto nerve entrapment. Nine feet were treated.

The Visual Analogue Scale (VAS) is a 0 to 10 scale in which subjectsrated pain. No pain equals zero and 10 equals very severe pain. The VASwas used by Subjects to assess pain pre-treatment, immediatelypost-treatment, at Day 7 and at Day 30.

Duration of treatment was assessed at Day 7, Day 30 and Day 56. At thesetime points, Subjects were asked if they were having an effect from thetreatment. The Post-Treatment Questionnaire included 2 questionsregarding subject satisfaction. Subjects were asked if he/she wouldrecommend the treatment to a family member and would he/she have thetreatment again if available. Both questions were answered with either ayes or a no.

Following the application of local anesthetic, the cryoprobe wasinserted into the epidermis and advanced to the depth of the targetednerve. Figs. The associated sensory nerves may be in a treatment areadistal to the superior extensor retinaculum (e.g., proximal portion ofthe anterior annular ligament) and may include: the intermediate,lateral, and medial dorsal cutaneous nerves; the sural nerve; thebranches of the tibial nerve; and/or the deep peroneal nerve. A15-second pre-warming phase was followed by treatment delivered for 60seconds and a 10 second post-warming period, completed after treatment.Collectively this is described as a treatment cycle. The treatment wasplaced by first identifying the neuroma or area of focused pain bypalpating the forefoot to identify the area of pain. After the treatmentcycle was completed, the probe was placed adjacent to the previoustreatment site to form a series of treatments across the pathway of thetarget nerve branch.

Seven Subjects were enrolled in the study and nine feet were treated.Table 1 provides an overview of subject accountability. Subjects with adiagnosis of bilateral forefoot pain due to nerve entrapment wereeligible for a bilateral treatment. Two Subjects received bilateraltreatment while five Subjects received unilateral treatment.

TABLE 1 Subject accountability overview Status Site 16 Site 18 TotalEnrolled 3 4 7 Discontinued-subject withdrawal 0 0 0Discontinued-investigator 0 0 0 withdrawal Excluded for ProtocolViolation 0 0 0 Total Included in Data Analysis 3 4 7

Subject accountability for required follow-up visits on Day 7 and Day 30was 100% and 71% for the required follow-up visit at Day 56. The Day 56follow-up visits were not done for Subjects 16-005 and 18-001. NoSubjects were followed beyond Day 56. Table 2 provides an overview ofsubject accountability over follow-up periods. Subject 18-004 had anincomplete visit at Day 56; adverse event status and medicationsinformation were not collected.

TABLE 2 Subject Accountability over follow-up period Site Day IDEnrolled Treated Day 7 30 Day 56 16 3 3 3 3 2 18 4 4 4 4 3

Demographics—Of the Subjects enrolled, 57% (4/7) were male and 43% (3/7)were female. The average age was 54.6 years old (range 29-66 years old)with a standard deviation 12.1. The average VAS score at baseline was6.3 (standard deviation 0.9). Demographics are detailed below in Table3.

TABLE 3 demographics Total Gender (% M/% F) 57%/43% Average age 54.6(Standard deviation, range) (12.1, 29-66) Average BMI 29.3 (Standarddeviation) (3.6) Race 71% White (Subject reported) 14% Native Hawaiianor Other Pacific Islander 14% Not reporting Average baseline VAS 6.3(Standard deviation) (0.9)

The cryogenic cooling device was used on awake subjects who wereprepared with dermal anesthesia only. Local anesthesia was injected intotarget site with the goal of complete cutaneous anesthesia at the targettreatment area prior to the treatment. All subjects received treatmentswith the Cryo-Touch III system, with either a 6 or 12 mm uncladdedcryoprobe based on the Investigator's discretion. Anatomical landmarksand palpitation for pain were used to guide treatment locations.Landmarks comprised of palpation of metatarsal bones to locateintervening metatarsal spaces consistent with the target nerve pathway.Treatment algorithms were the same between sites. The sole differencewas in treatment approach; at Site 16, the Investigator chose toapproach the nerve dorsally, and at Site 18, the Investigator used aplantar approach. Subjects received an average of 3.7 insertions perside treated.

Effectiveness Results—VAS scores were analyzed for improvement in pain;response rates, minimal clinically important differences andstatistically significant improvements from baseline were assessed ateach follow-up point. Duration of treatment effect was analyzed fornumber of responders at each follow-up point. All averages calculatedinclude the standard deviation parenthetically to better describe thestatistical outcomes of this analysis.

VAS Score—Seventy-one percent (71%) of Subjects reported improvement inVAS at Day 7. Table 4 shows the percent of subjects with improvements inVAS score from the baseline. VAS scores were also assessedpost-treatment and again at Day 30, with 100% (7/7) of subjectsreporting improvement in VAS immediately post-treatment and 71% (5/7)with improvement at Day 30. The minimal clinically important difference(MCID) in VAS is 1.3 on the 0-100 mm scale, corresponding to a ≥2 pointimprovement on the 0-10 VAS scale used in this study. The percentage ofSubjects showing a MCID in VAS was 100% (7/7) post-treatment, 71% (5/7)at Day 7 and 71% (5/7) at Day 30.

TABLE 4 Percent of subjects with improvement in VAS score from baseline.Post Treatment Day 7 Day 30 ≥1 point improvement 100% (7/7) 71% (5/7)71% (5/7) ≥2 point improvement (MCID) 100% (7/7) 71% (5/7) 71% (5/7)

When assessed post-treatment, VAS scores improved by an average of 5.9points (Table 5), an average of a 94% improvement from baseline. Table 5shows the average improvement in VAS score from baseline. At Day 7,Subjects had an average VAS score improvement of 2.4 points, a 38%improvement from baseline. At Day 30 post-treatment, Subjects had anaverage VAS score improvement of 3 points, a 45% improvement compared tobaseline.

Improvements in VAS scores from baseline to each time point wereanalyzed for statistical significance using a null hypothesis of Ho:Difference=0, where the difference is calculated by subtracting thescore at post-treatment, Day 7 and Day 30 from the VAS score reported atbaseline. A paired two-tailed t-test was employed to account for thepossibility of subjects worsening over the course of the study, and thetest was performed using a statistical significance level of P<0.05. Thepoint improvements from baseline at post-treatment, Day 7 and Day 30were tested against the null hypothesis and produced P-values of5.10E-07, 0.03, and 0.61, respectively (Table 5). The P-values forpost-treatment and Day 7 meet the threshold of statistical significance(P<0.05) and reject the null hypothesis of zero change from baseline.The analysis shows a statistically significant change in the VAS scoresfrom baseline to these follow-up assessments. The P-value for the Day 30results (0.61) does not meet the threshold of statistical significance(P<0.05) and therefore does not show a statistically significant changein VAS scores from baseline to the Day 30 follow-up.

Duration of Treatment Effect—Duration of treatment effect was assessedfor subjects at Day 7, Day 30 and Day 56 on a per Subject basis.Additional duration of treatment assessments were completed viatelephone call every four weeks until the Subject reported no effect upto 112 days post-treatment. At Day 7, 5/7 subjects (71%) reportedcontinued effect from treatment (Table 6). Table 6 shows subjectsreporting continued effect from treatment over initial follow-up period.At Day 30, 5/7 subjects (71%) reported continued effect from treatment.At Day 56, 3/5 subjects (60%) reported continued effect. Only oneSubject was followed beyond Day 56 (see Section 5.5 Deviations from TheInvestigational Plan).

TABLE 6 Subjects reporting continued effect from treatment over initialfollow-up period. Day 7 Day 30 Day 56 Reporting Effect 71% (5/7) 71%(5/7) 60% (3/5) from Treatment

Subjects completed the post-treatment questionnaire at Day 7 and Day 30post-treatment visits. The questionnaire assessed subject satisfaction,subject experience with anticipated observations and subject's pain fromtreatment. The responses for subject satisfaction are shown in Table 7below. At both Day 7 and Day 30, 5/7 Subjects (71%) said they wouldrecommend the treatment to a family member. Similarly, 4/7 subjects(57%) would have the treatment again when asked at Day 7 and 5/7 (71%)said they would have the treatment again at Day 30.

TABLE 7 Subject Satisfaction Day 7 Day 30 Would you recommend this 71%71% treatment to a family member? (% (5/7) (5/7) Yes) Would you havethis treatment 57% 71% again? (% Yes) (4/7) (5/7)

Subject experience with anticipated observations was assessed; theresults are described in Table 8 below. The data below reflect how theSubjects responded to the question.

TABLE 8 Subject Reported anticipated observations Day 7 Day 30 Did thesubject report any anticipated 86% (6/7) 57% (4/7) observations? (% Yes)If yes, how much 1 (AO had very negative impact) 17% (1/6) 25% (1/4) didthey/it impact 2  0% (0/6)  0% (0/4) subject's daily 3 17% (1/6)  0%(0/4) routine? 4  0% (0/6) 25% (1/4) 5 (No impact at all) 67% (4/6) 50%(2/4)

The Subject who rated their anticipated observations as having verynegative impact reported severe tingling and moderate local pain at Day7. At Day 30, the tingling had improved to moderate while pain remainedmoderate. This Subject did not complete a Day 56 visit.

Subjects were also asked if pain was present from treatment and if so,to rate it on a 1-5 scale. The results are shown below in Table 9.

TABLE 9 Subject reported pain from treatment Day 7 Day 30 Is there anypain present from 71% (5/7) 29% (2/7) treatment? (% Yes) If yes, enterscale 1 (Not at all painful)  0% (0/5) 50% (1/2) 2 60% (3/5) 50% (1/2) 320% (1/5)  0% (0/2) 4 20% (1/5)  0% (0/2) 5 (Very painful)  0% (0/5)  0%(0/2)

Entrapped nerves may be treated at the point of entrapment or proximalthereto. Wallerian degeneration of the nerve axons following focusedcold therapy suspends conduction of entrapped nerve pain. Further,resulting inflammation may address the mechanism of entrapment so whenthe nerve axons regenerate they may no longer be entrapped and thechronic pain may not return.

Based on the high treatment response rate, a 27 ga 6-12 mm cryoprobelength for treatment of foot pain is possible. With needles less than 7mm in length, larger gauge needles (smaller diameter) may be preferredso as to limit mechanical injury to the skin and tissue to be treated.For example, in some embodiments, it may be beneficial to use 27 gaugeneedles.

Optionally, longer needles may be used in some embodiments (e.g., 8-15mm, 20 mm, 90 mm etc.). Longer needles may require a smaller gauge(larger diameter) needle so they have sufficient rigidity to maintainconsistent spacing when placed deep in the tissue, but not so large asto create significant mechanical injury to the skin and tissue wheninserted (e.g., greater than 20 ga). Alternate configurations of thedevice may have two or more needles spaced generally 3-5 mm apart oflengths ranging from up to 20 mm or greater, typically of 25 gauge or 23gauge. Single needle configurations may be even longer (e.g., 90 mm) forreaching target tissues that are even deeper (e.g., >15 mm or so belowthe dermis). Longer needle devices (e.g., >10 mm) may not need activeheating of the skin warmer and/or cladding found in designs usingshorter needle(s) as the cooling zone may be placed sufficiently deepbelow the dermis to prevent injury. In some embodiments, devices withsingle long needle configurations may benefit from active nerve locationsuch as ultrasound or electrical nerve stimulation to guide placement ofthe needle. Further, larger targets may require treatment from bothsides to make sure that the cold zone created by the needle fully coversthe target. Adjacent treatments placing the needle to either side of anerve during two successive treatment cycles may still provide aneffective treatment of the entire nerve cross-section.

In some situations, a probe with multiple spaced apart needles may bepreferable (e.g., 2, 3, 4 or more). A device employing multiple needlesmay decrease the total treatment duration by creating larger coolingzones. Further, a multi-needle device may be configured to providecontinuous cooling zones between the spaced apart needles. In someembodiments, the needles may be spaced apart by 1-5 mm. The spacing maybe dependent on the type of tissue being targeted. For example, whentargeting a nerve, it may be preferable to position the nerve betweenthe two or more needles so that cooling zones are generated on bothsides of the nerve. Treating the nerve from both sides may increase theprobability that the entire cross-section of the nerve will be treated.For superficial peripheral nerves, the nerves may be at depths rangingfrom 2-6 mm and may be smaller in diameter, typically <2 mm.Accordingly, devices for treating foot pain and/or Morton's neuroma orother superficial peripheral nerves may comprises two or more 27 gaugeneedles spaced ≤2 mm apart and having typical lengths less than 7 mm(e.g., 6.9 mm); however longer needles may be required to treat the fullpatient population in order to access patients with altered nerveanatomy or patients with higher amounts of subcutaneous tissue such asthose with high BMIs. Neuroma treatment may involve treating the neuromadirectly. In some embodiments, it may be preferable to treat proximal tothe neuroma so as to lead to a longer period of time required for nerveaxon degeneration followed by nerve axon regeneration in the vicinity ofthe neuroma. Advantageously, focused cold therapy may relieve painassociated with neuroma in addition to reducing the size of the neuromato relieve and/or cure the symptom.

Such treatments may also reduce the amount of drug therapy required,postpone invasive surgeries, and may provide an opportunity for physicalrehabilitation (e.g., strength, flexibility, etc.). Furthermore theprocedure may be used either pre- or post-operatively. Before total kneereplacement surgery, the procedure may be used to limit pain, allowpatients to strengthen the joint which may improve surgical outcomes.Post surgically, the procedure may be used to limit the use of opioidsor other pain killers and or allow the patient to reduce residualpost-surgical pain.

While the study used a treatment cycle comprising a 10 second pre-warmphase, followed by a 60 second cooling phase, followed thereafter by a15 second post-warm phase with 40° C. skin warmer throughout, it shouldbe understood that other treatment cycles may be implemented. In someembodiments, a pre-warming cycle can range from 0 to up to 30 seconds,preferably 5-15 seconds sufficient to pre-warm the cryoprobe andopposing skin. Treatment cooling may range from 5-120 seconds,preferably 15-60 seconds based on the flow rate, geometry of thecryoprobe, size of the therapy zone, size of the target nerve or tissueand the mechanism of action desired. Post warming can range from 0-60seconds, preferably 10-15 seconds sufficient to return the cryoprobe toa steady state thermal condition and possibly to free the cryoprobeneedle(s) from the frozen therapy zone (e.g., at least 0° C.) prior toremoving the cryoprobe needles. For example, in some embodiments,devices with 6.9 mm long cladded needles may be warmed with a 30° C.heater. The treatment cycle may comprise a 10 second pre-warm phase, a35 second cooling phase, and a 15 second post-warm phase.Advantageously, such a treatment cycle may make an equivalent cryozoneas the treatment cycle used in the study in a shorter amount of time(e.g., a 35 second cooling phase compared to a 60 second cooling phase).

In some embodiments, treatment devices and treatment cycles may beconfigured to deliver a preferred cryozone volume. For example, in someembodiments, devices and treatment cycles may be configured to generatecryozones (defined by the 0 degree isotherm) having a cross-sectionalarea of approximately 14-55 mm² (e.g., 27 mm²). Optionally, the devicesand treatment cycles may be configured to generate cryozones having avolume of approximately 65-125 mm³ (e.g., 85 mm³).

Accordingly, in some embodiments, treatment cycles may be configuredwith cooling phases ranging between 15-75 seconds (e.g., 30 seconds, 35seconds, 40 seconds, 45 seconds, etc.) depending on cooling fluid flowrates, warming phase durations, warming phase temperature, number ofcooling needles, needle spacing, or the like in order to generate adesired cryozone. Similarly, treatment cycles may be configured withwarming phases operating a temperatures ranging between 10-45° C.depending on the length of cooling phases, number of needles, needlespacing, etc. in order to generate a desired cryozone. Generally, withhigher degree warming phases, the duration of the pre-warm phase and thecooling phase will be longer, however the post-warm phase duration maybe reduced. In some embodiments the temperature can be set to onetemperature during the pre-warm phase, another temperature during thecooling phase, and a third temperature during the post-warm phase.

In some embodiments, devices may be configured to limit flow rate of acooling fluid to approximately 0.34-0.80 SLPM (gas phase). Optionally,in some embodiments, it may be preferable to configure the device andthe treatment cycle to maintain the tip a less than −55° C. duringcooling phases. In some embodiments, it may be preferable to configurethe device and the treatment cycle to have the tip return to at least 0°C. at the end of the post-warm phase so as to ensure the device may besafely removed from the tissue after the treatment cycle.

While generally describing treatment cycles as includingpre-heating/warming phases, it should be understood that other treatmentcycles may not require a pre-heating/warming phase. For example, largerneedle devices (e.g., 30-90 mm) may not require a pre-heat/warm phase.Larger needles may rely on the body's natural heat to bring the needleto a desired temperature prior to a cooling phase.

Although the above described procedures treated foot pain using cold,other methods and devices could be used to temporarily or permanentlydisable neuromas or fibromas. Examples include thermal nerve ablationsuch as with RF energy, or neurolysis using injections of phenol orethyl alcohol.

In some embodiments of the present invention, treatment guidance canrely on rigid or boney landmarks because they are less dependent uponnatural variations in body size or type, e.g. BMI. Soft tissues,vasculature and peripheral nerves pass adjacent to the rigid landmarksbecause they require protection and support. The target nerve to relievepain can be identified based on the diagnosis along with patientsidentifying the area of pain, biomechanical movements that evoke painfrom specific areas, palpation, and diagnostic nerve blocks using antemporary analgesic (e.g. 1-2% Lidocaine). Target nerve (tissue) can belocated by relying on anatomical landmarks to indicate the anatomicalarea through which the target nerve (tissue) reside. Alternatively,nerve or tissue locating technologies can be used. In the case ofperipheral nerves, electrical stimulation or ultrasound can be used tolocate target nerves for treatment. Electrical nerve stimulation canidentify the nerve upon stimulation and either innervated muscle twitchin the case of a motor nerve or altered sensation in a specific area inthe case of a sensory nerve. Ultrasound is used to visualize the nerveand structures closely associated with the nerve (e.g. vessels) toassist in placing the cryoprobe in close proximity to the target nerve.By positioning the patient's skeletal structure in a predeterminedposition (e.g. knee bent 30 degrees or fully extended), one can reliablyposition the bones, ligaments, cartilage, muscle, soft tissues(including fascia), vasculature, and peripheral nerves. Externalpalpation can then be used to locate the skeletal structure and therebylocate the pathway and relative depth of a peripheral nerve targeted fortreatment.

A treatment of peripheral nerve tissue to at least −20° C. is sufficientto trigger 2nd degree Wallerian degeneration of the axon and mylinatedsheath. Conduction along the nerve fibers is stopped immediatelyfollowing treatment. This provides immediate feedback as to the locationof the target peripheral nerve or associated branches when theassociated motion or sensation is modified. This can be used to refinerigid landmark guidance of future treatments or to determine whetheraddition treatment is warranted.

By using rigid landmarks, one may be able to direct the treatmentpattern to specific anatomical sites where the peripheral nerve islocated with the highest likelihood. Feedback from the patientimmediately after each treatment may verify the location of the targetperipheral nerve and its associated branches. Thus, it should beunderstood that in some embodiments, the use of an electronic nervestimulation device to discover nerve location is not needed or used,since well-developed treatment zones can locate target nerves. This maybe advantageous, due the cost and complexity of electronic nervestimulation devices, which are also not always readily available.

In alternative embodiments of the invention, one could use an electronicnerve stimulation device (either transcutaneous or percutaneous) tostimulate the target peripheral nerve and its branches. Withtranscutaneous electric nerve stimulation (TENS) the pathway of thenerve branch can be mapped in an X-Y coordinates coincident with theskin surface. The Z coordinate corresponding to depth normal to the skinsurface can be inferred by the sensitivity setting of the electricalstimulation unit. For example, a setting of 3.25 mA and pulse durationof 0.1 ms may reliably stimulate the frontal branch of the temporalnerve when it is within 7 mm of the skin surface. If a higher currentsetting or longer pulse duration is required to stimulate the nerve,then the depth may be >7 mm. A percutaneous electrical nerve stimulator(PENS) can also be used to locate a target peripheral nerve. Based onrigid anatomical landmarks, a PENS needle can be introduced through thedermis and advanced into the soft tissues. Periodic stimulating pulsesat a rate of 1-3 Hz may be used to stimulate nerves within a knowndistance from the PENS needle. When the target nerve is stimulated, thesensitivity of the PENS can be reduced (e.g. lowering the currentsetting or pulse duration) narrowing the range of stimulation. When thenerve is stimulated again, now within a smaller distance, the PENSsensitivity can be reduced further until the nerve stimulation distanceis within the therapy zone dimensions. At this point, the PENS needlecan be replaced with the focused cold therapy needle(s) and a treatmentcan be delivered. The PENS and focused cold therapy needles can beintroduced by themselves or through a second larger gage needle orcannula. This may provide a rigid and reproducible path when introducinga needle and when replacing one needle instrument with another. A rigidpathway may guide the needle to the same location by preventing needletip deflection, which could lead to a misplaced therapy and lack ofefficacy.

While many of the examples disclosed herein related to puncturing theskin in a transverse manner to arrive at a target sensory nerve, othertechniques can be used to guide a device to a target sensory nerve. Forexample, insertion of devices can be made parallel to the surface of theskin, such that the (blunted) tip of the device glides along aparticular fascia to arrive at a target sensory nerve. Such techniquesand devices are disclosed in U.S. Pub. No. 2012/0089211, the entirety ofwhich is incorporated by reference. Possible advantages may include asingle insertion site, and guidance of a blunt tip along a layer commonwith the path or depth of the target nerve. This technique may be aposition-treatment—thaw, reposition treatment, thaw, etc.

While the exemplary embodiments have been described in some detail forclarity of understanding and by way of example, a number ofmodifications, changes, and adaptations may be implemented by persons ofordinary skill in the art after reading the disclosure provided herein.Hence, the scope of the present invention is limited solely by theclaims as follows.

What is claimed is:
 1. A system for treating a neuroma in a limb of apatient, the system comprising: a needle having a proximal end, a distalend, and a needle lumen therebetween, the needle configured forinsertion proximate to the nerve; a cooling fluid supply lumen extendingdistally within the needle lumen to a distal portion of the needlelumen; a cooling fluid source couplable to the cooling fluid supplylumen to direct cooling fluid flow into the needle lumen so that liquidfrom the cooling flow vaporizes within the needle lumen to providecooling to the nerve such that neuroma decreases in size and/or painassociated with the neuroma and experienced by the patient is reduced.2. The system of claim 1, wherein the cooling flow vaporizes within theneedle lumen to provide a cryozone having a cross-sectional area between14-40 mm², the cryozone being defined by a 0° C. isotherm.
 3. The systemof claim 1, wherein the cooling flow vaporizes within the needle lumento provide a cryozone having a volume between 65-105 mm³, the cryozonebeing defined by a 0° C. isotherm.
 4. The system of claim 1, furthercomprising: a heating element coupled with a proximal portion of theneedle, the heating element configured to deliver heating phases to theskin of the patient; and a processor configured to control the coolingfluid flow and the heating element in response to operator input, theprocessor configured to provide a treatment cycle in response to atreatment instruction, the treatment cycle comprising at least oneheating phase and one cooling phase.
 5. The system of claim 3, whereinthe processor is further configured to provide a degree of skin warmerthroughout the treatment cycle.
 6. The system of claim 5, wherein thedegree of skin warmer comprises 28-42° C. skin warmer throughout thetreatment cycle.
 7. The system of claim 3, wherein the at least oneheating phase comprises a pre-warm phase with the heating element beforethe at least one cooling phase.
 8. The system of claim 6, wherein thepre-warm phase has a duration of 8-12 seconds.
 9. The system of claim 6,wherein the at least one cooling phase has a duration of 20-65 seconds.10. The system of claim 8, wherein the at least one cooling phase has aduration of less than 40 seconds, and wherein the at least one coolingphase creates a cryozone having a cross-sectional area between 14-40mm², the cryozone being defined by a 0° C. isotherm.
 11. The system ofclaim 8, wherein the at least one cooling phase has a duration of lessthan 40 seconds, and wherein the at least one cooling phase creates acryozone having a volume between 65-105 mm³, the cryozone being definedby a 0° C. isotherm.
 12. The system of claim 8, wherein the at least oneheating phase further comprises a post-warm phase.
 13. The system ofclaim 11, wherein the post-warm phase has a duration of 12-18 seconds,and wherein the distal portion of the needle has a temperature of atleast 0° C. at the end of the post-warm phase.
 14. The system of claim1, wherein the needle comprises a length of 5-14 mm.
 15. The system ofclaim 1, wherein the processor is configured to provide an audio orvisual alert at completion of a treatment cycle.